1. Field of the Invention
This invention relates to selected 6-alkyl-5-[4(alkylsulfinyl or alkylsulfonyl)phenyl]-2(1H)-pyridinones, their use as cardiotonics and their preparation.
2. Description of the Prior Art
Shen et al [U.S. Pat. No. 3,655,679, issued Apr. 11, 1972] show as anti-inflammatory agents various arylhydroxy-pyridinecarboxylic acids including 5-aryl-2-hydroxynicotinic acids where aryl is, inter alia, phenyl containing one or more R substituents which may be at any position on the ring (preferably at the 4-position), said substituents including "alkyl . . . , alkenyl . . . , halogen . . . , haloalkyl . . . , hydroxy, alkoxy . . . , acyloxy . . . , nitro, amino, alkylamino . . . , dialkylamino . . . , acylamino . . . , mercapto, alkylthio (preferably lower alkylthio such as methylthio, ethylthio, etc.), alkylsulfonyl (preferably lower alkylsulfonyl such as methylsulfonyl), or alkylsulfinyl (preferably lower alkylsulfinyl such as methylsulfinyl)". Shown in Table I of Example 55 is 5-(p-methylthiophenyl)-2-hydroxynicotinic acid. Shown as intermediates for these 5-aryl-2-hydroxynicotinic acids, which tautomerically can be designated as 3-carboxy-5-aryl-2(1H)-pyridinones, are various 5-aryl-2-hydroxynicotinonitriles (Table I of Example 48 where aryl is shown, inter alia, to be p-mercaptophenyl and p-methylsulfonylphenyl). Also shown as intermediates for said acids are various methyl 5-aryl-2-hydroxy-6-methylnicotinates (Table I of Example 50 where aryl is shown, inter alia, to be p-methoxyphenyl) and corresponding 5-aryl-2-hydroxy-6-methylnicotinonitriles (last paragraph of Example 50). Also shown in this patent (paragraph common to columns 50 and 51) is the oxidation of 2-(4-methylthiophenyl)-5-hydroxyisonicotinic acid with sodium metaperiodate to produce 2-(4-methylsulfinylphenyl)-5-hydroxyisonicotinic acid.
Shen et al [U.S. Pat. No. 3,718,743, issued Feb. 27, 1973] show "5-phenyl-2-piperidinones and 5-phenyl-2-thiopiperidinones in compositions and methods for treating pain, fever and inflammation". The generic teaching of these piperidinones shows that "phenyl" can have one or two substituents at positions 2, 3, 4, 5 and/or 6, including alkyl, halogen, haloalkyl, aryl, nitro, amino, acylamino, acyl, carboxy, carbalkoxy, carbamyl, dialkylsulfamyl, alkylamino, dialkylamino, alkylmercapto, alkylsulfinyl and alkylsulfonyl. Various means of preparing the 5-phenyl-2-piperidinone final products are shown. In one procedure, a 2-chloro-5-phenylpyridine is heated with aqueous sodium hydroxide in dimethylformamide to produce the corresponding 5-phenyl-2(1H)-pyridinones which are then hydrogenated to produce the desired 5-phenyl-2-piperidinones. Among the intermediate 5-phenyl- 2(1H)-pyridinones specifically shown is 5-(4-methoxyphenyl)-2(1H)-pyridinone and its conversion by heating with pyridine hydrochloride under nitrogen to produce the corresponding 5-(4-hydroxyphenyl)-2(1H)-pyridinone.
Merck and Co. [British Pat. No. 1,238,959, published July 14, 1971] show as antiinflammatory agents 3(or 4)-aryl-2(1H)-pyridinones where "aryl" is, inter alia, phenyl which can be mono- or di-substituted by a variety of groups including "alkyl, phenyl, halogen, trihaloalkyl, alkoxy, amino, dialkylamino, nitro, cyano, sulfamoyl, alkylsulfamoyl, dialkylsulfamoyl, hydroxy, mercapto, alkylthio, alkylsulfinyl, alkylsulfonyl, carbamoyl, carboxy, sulfo or phenylsulfonyl". Specifically shown, inter alia, as Examples 33 and 34 are 3-(4-methylsulfinylphenyl)-2(1H)-pyridinone and 3-(4-methylsulfonylphenyl)-2(1H)-pyridinone, which were prepared by oxidation of 3-(4-methylthiophenyl)-2(1H)-pyridinone with sodium metaperiodate and aqueous hydrogen peroxide, respectively.
Sandoz AG [U.K. Patent Application No. 2,070,606, published Sept. 9, 1981] show as intermediates 3-cyano-6-R.sub.2 -5-aryl-2(1H)-pyridinones where R.sub.2 is hydrogen or lower-alkyl and aryl is, inter alia, 4-methoxyphenyl. These compounds are reportedly prepared by reacting cyanoacetamide with 4-dimethylamino-3-aryl-3-buten-2-one and are converted in turn to the corresponding 3-carbamyl and then 3-amino compounds, the latter compounds reported to be cardiotonic agents.
Lesher, Opalka and Page [U.S. Pat. No. 4,276,293, issued June 30, 1981] show as intermediates 3-cyano-6-(lower-alkyl)-5-(pyridinyl)-2(1H)-pyridinones which are prepared by reacting a 1-(pyridinyl)-2-(dimethylamino)ethenyl lower-alkyl ketone with .alpha.-cyanoacetamide and conversion thereof, by hydrolysis and decarboxylation, to the corresponding 6-(lower-alkyl)-5-(pyridinyl)-2(1H)-pyridinones.
Lesher and Philion [U.S. Pat. No 4,313,951, issued Feb. 2, 1982 from application Ser. No. 198,461, filed Oct. 20, 1980 as a continuation-in-part of application Ser. No. 97,504, filed Nov. 26, 1979 and now abandoned] disclose as cardiotonics, inter alia, 3-cyano-6-(lower-alkyl)-5-(pyridinyl)2(1H)-pyridinones and their preparation, and also the conversion by hydrolysis of said 3-cyano compounds to the corresponding 3-carbamyl compounds and subsequent conversion of the latter to the corresponding cardiotonically active 3-amino-6-(lower-alkyl)-5-(pyridinyl)-2(1H)-pyridinones.
Lesher, Opalka and Page [U.S. Pat. No. 4,312,875, issued Jan. 26, 1982] disclose 6-(lower-alkyl)-5-(pyridinyl)-2(1H)-pyridinones as cardiotonics.